Method of coating a stent having variable drug release rate

ABSTRACT

A method of coating a stent may comprise applying a composition including a drug and a polymer to the stent to form a coating. The release rate of the drug from the coating gradually increases along a length of the stent which extends axially from opposite ends of the stent. The variable drug release rate can be accomplished by varying the coating thickness, by applying a barrier region over the drug-containing composition, and/or by having different polymers in the coating, the polymers having different drug permeabilities.

CROSS REFERENCE TO RELATED APPLICATION

This is a divisional of U.S. application Ser. No. 11/595,736, filed Nov.8, 2006, now U.S. Pat. No. 7,820,229, which is a divisional of Ser. No.10/293,658, filed Nov. 12, 2002, now U.S. Pat. No. 7,169,178, the entirecontents of both applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to an implantable device, such as a stent,having a polymeric drug coating, and method of forming the same.

2. Description of the Background

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to remodel the vessel wall.The balloon is then deflated to a smaller profile to allow the catheterto be withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings, which can collapse and occludethe conduit after the balloon is deflated. Vasospasms and recoil of thevessel wall also threaten vessel closure. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may necessitate another angioplasty procedure or asurgical by-pass operation. To reduce the partial or total occlusion ofthe artery by the collapse of arterial lining and to reduce the chanceof the development of thrombosis and restenosis, an expandable,intraluminal prosthesis, also known as a stent, is implanted in thelumen to maintain the vascular patency.

Stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed so that they can be inserted through smalllumens via catheters and then expanded to a larger diameter once theyare at the desired location. Mechanical intervention via stents hasreduced the rate of restenosis as compared to balloon angioplasty. Yet,restenosis is still a significant clinical problem with rates rangingfrom 20-40%. When restenosis does occur in the stented segment, itstreatment can be challenging, as clinical options are more limited ascompared to lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a drug at the diseased site. In order to providean efficacious concentration to the treated site, systemicadministration of such medication often produces adverse or even toxicside effects for the patient. Local delivery is a preferred method oftreatment in that smaller total levels of medication are administered incomparison to systemic dosages, but are concentrated at a specific site.Local delivery thus produces fewer side effects and achieves morefavorable results.

One proposed method of medicating stents involves the use of a polymericcarrier coated onto the surface of the stent. A composition including asolvent, a polymer dissolved in the solvent, and a drug dispersed in theblend is applied to the stent by immersing the stent in the compositionor by spraying the composition onto the stent. The solvent is allowed toevaporate, leaving on the stent surfaces a coating of the polymer andthe drug impregnated in the polymer.

A potential shortcoming of conventional medicated stents is that therecan be an unequal release of the drug to different areas of thetreatment site. For instance, in conventional stents, the concentrationof the drug on the stent is essentially constant along the length of thestent. In such drug delivery stents, after the stent is implanted in thebiological lumen and the drug is released from the polymeric matrix, theconcentration of the drug that is applied to the tissues along thelength of the stent will not be constant along the length of the stent.In particular, the drug concentration in the blood stream is higher inthe distal region of the biological lumen than the proximal region.

Referring to FIG. 1, a stent 10 with a polymeric drug coating isimplanted into a biological lumen 12, which has a proximal region 14 anda distal region 16. The blood in biological lumen 12 flows from proximalregion 14 to distal region 16 as the drug is released from the polymericcoating. If the quantity and release rate of the drug are constant overthe length of stent 10, when stent 10 is first implanted into biologicallumen 12, the drug concentration in the blood will be constant along thelength of stent 10 as graphically illustrated in FIG. 2A. As shown inFIG. 2B, however, over time more drug is released into the blood streamand the drug concentration in the blood in distal region 16 becomessignificantly higher as compared to the drug concentration in proximalregion 14. As a result, depending on the biological needs of the tissuein the respective regions, the tissue in distal region 16 can receivetoo much drug whereas the tissue in proximal region 14 may not receiveenough drug.

Another example of a related shortcoming of conventional medicatedstents is that there can be an unequal release of the drug to thetissues adjacent to the points of contact between the stent and thetissues. Referring to FIG. 1, stent 10 can have a tubular body ofstructural members including struts 18 and connecting elements 20 thatform a network structure. Struts 18 are radially expandable andinterconnected by connecting elements 20 that are disposed betweenadjacent struts 18. Both struts 18 and connecting elements 20 have anouter (or lumen contacting) surface and an inner surface.

In conventional stents, the concentration of drugs on the stent isessentially constant along the length of struts 18 and connectingelements 20, including any curved or bent segments. Referring to FIG. 3,when stent 10 is inserted into a biological lumen, stent 10 formsmultiple contact points 30 with the tissue as shown with lines A-A andB-B. As the drug in the polymer is released from multiple contact points30 to the tissue, delivery zones 32 are formed. If the quantity of thedrug is the same along lines A-A and B-B, then some of delivery zones32, for example delivery zone 32A, overlap. As a result, the tissue areaadjacent to the overlapping delivery zones receives a greater quantityof drug than other tissue areas. Therefore, some tissue adjacent tocontact points 30 may receive too much drug.

Accordingly, what is needed is a coating for a stent that addresses theaforementioned drawbacks.

SUMMARY OF THE INVENTION

Briefly and in general terms, the present invention is directed to amethod of coating a stent.

In aspects of the invention, a method comprises applying a compositionincluding a drug and a polymer to the stent to form a coating, whereinthe release rate of the drug from the coating gradually increases alonga length of the stent, the length extending axially from opposite endsof the stent.

In other aspects, the composition is applied so that a thickness of thecoating decreases along the length of the stent.

In other aspects, the thickness of the coating is varied along thelength of the stent by masking portions of the stent during the applyingof the composition.

In other aspects, the method further comprising applying to the stent abarrier region over the composition, the barrier region is applied sothat the thickness of the barrier region decreases along the length ofthe stent.

In other aspects, the coating comprises different polymers havingdifferent drug permeabilities along the length of the stent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a side view of a conventional stent inserted into a biologicallumen;

FIGS. 2A and 2B are graphs of drug concentrations in blood along thelength of the stent illustrated in FIG. 1;

FIG. 3 is an enlarged view of a portion of the stent illustrated in FIG.1;

FIG. 4 is a side view of one embodiment of a stent of the presentinvention inserted into a biological lumen;

FIG. 5 is a graph of the drug concentration in a stent coating along thelength of the stent in accordance with one embodiment of the invention;

FIGS. 6A and 6B are graphs of drug concentrations in blood along thelength of the stent illustrated in FIG. 4;

FIG. 7 is a cross-section along line 7-7 in FIG. 4; and

FIGS. 8 and 9 are an enlarged views of a portion of the stentillustrated in FIG. 4 in accordance with embodiments of the invention.

DETAILED DESCRIPTION Variable Drug Concentration or Release Rate Alongthe Length of the Stent

The present invention is directed to a stent with a polymeric drugcoating having a variable drug concentration or release rate along thelength of the stent. Referring to FIG. 4, for example, a stent 40 coatedwith a polymeric drug coating can have a first segment 42, a secondsegment 44 and a third segment 46 along the length of stent 40, disposedbetween a first end 48 and a second end 50. In an embodiment of thepresent invention, the drug concentration in the coating gradually orincrementally increases along the length of stent 40 from first end 48to second end 50. FIG. 5, for example, graphically illustrates a drugconcentration in a coating that gradually increases along the length ofa stent from the distal end of stent 40 to the proximal end of stent 40.The increase of the drug concentration can also be graphicallyillustrated to be linear or stepwise/incremental. In another embodimentof the present invention, the release rate of the drug from the coatinggradually or incrementally increases along the length of stent 40 fromfirst end 48 to second end 50.

By varying the drug concentration in the polymeric coating, or therelease rate of the drug from the polymeric coating, the presentinvention advantageously provides a coating that provides uniform drugdelivery to the target site along the length of stent 40. Thedistribution of the drug in the blood stream along the length of thestented portion of the biological lumen depends on the Peclet numberwhich is defined as

${Pe} = \frac{VL}{D}$where V is the velocity of the blood stream, L is the length of thestented portion of the lumen, and D is the diffusivity of the drug inthe blood stream. In essence, the Peclet number is the ratio of theconvection to diffusion. As can be understood by the above equation, ifthe velocity of the blood stream is relatively high in comparison to thediffusivity, then much of the drug released from the stent will becarried away by the blood flow from the treatment area adjacent to thestent. However, in a typical blood vessel, the Peclet number isrelatively low and diffusion dominated. As a result, the drug releasedfrom the stent will remain present in the blood stream at the localtreatment site and will be available for absorption by the arterialwall. This is especially advantageous for portions of the arterial wallsthat are not being contacted by the stent but are being contacted by theblood. However, the relatively low Peclet number in a typical bloodvessel results in a higher concentration of the drug in the blood streamin the distal region of the biological lumen as compared to the proximalregion if the drug concentration is uniform along the length of thestent.

A stent coated in accordance with the various embodiments of the presentinvention can provide a drug concentration in the blood that isinitially high in the proximal region of lumen 12, as graphicallyillustrated in FIG. 6A. However, as shown in FIG. 6B, over time moredrug is released into the blood stream and the drug concentration in theblood becomes uniformly distributed along the length of stent 40,providing for a beneficial long-term treatment regime.

Variable Drug Concentration or Release Rate Along the Circumference ofthe Stent

The present invention is also directed to a stent with a polymeric drugcoating having a variable drug concentration or release rate along thecircumference of the stent. A stent with such a coating can beparticularly suitable to use when it is known that one side of a lumenis in greater need of a drug than the other side. The coating can becustomized so that a targeted dose of the drug or a particular drug isdelivered to one side of the lumen.

The stent of the present invention, for instance, can have any suitablenumber of coating segments along the radial perimeter of the stent,where the concentration of the drug in the coating is higher alongselected segments as compared to other segments. FIG. 7 illustrates theradial perimeter of a stent with two coating segments. A first coatingsegment 60 extends from point E to point F, and a second coating segment62 extends from point G to point H. In an embodiment, the drugconcentration of the coating along first segment 60 can be greater thanthe drug concentration of the coating along second segment 62. Inanother embodiment, the release rate of the drug from the coating isgreater in first segment 60 as compared to second segment 62.

In another embodiment, the concentration of the drug in the coatinggradually increases along at least a portion of the radial perimeter ofthe stent. For example, referring to FIG. 7, the concentration of thedrug can gradually increase from point E to point G and from point F topoint H. Also, in an embodiment, the release rate of the drug from thecoating can gradually increase along at least a portion of the radialperimeter of the stent.

Variable Drug Concentration or Release Rate Along Struts of the Stent

The present invention is further directed to a stent with a polymericdrug coating having a variable drug concentration or release rate alongthe length of individual structural members of stent 40 such as struts52 and connecting members 54. In this way, the drug concentration orrelease rate on the individual structural members can be tailored tomatch the geometrical configuration of the stent structure. In otherwords, the coating can have a variable drug concentration or releaserate along the length of individual structural members to account forhow the structural members are positioned relative to one another in thestent structure, e.g., as deployed in the expanded state. Referring toFIG. 8, for instance, individual strut 52 or connecting member 54 canhave generally linear segments 70 that are interrupted by a curved orbent segment 72. In an embodiment, the concentration of the drug isgreater in at least a portion of curved segment 72 as compared to linearsegments 70. In another embodiment, the concentration of the drug isgreatest at the vertex of curved segment 72 of strut 52.

By coating a stent with a coating having a variable drug concentrationor release rate along the length of individual struts or connectingelements of the stent, a stent can carry a drug with delivery zones ofdifferent sizes for delivery of the drug to a selected portion of abiological lumen of a patient. “Delivery zones” refers to the region ofthe treatment site in which the drug is delivered, for example, bydiffusion. After a stent coated in accordance with the present inventionis inserted into a biological lumen of a patient, the delivery zoneswill not significantly overlap. Referring to FIG. 9, if theconcentration of the drug is lower along the line C-C than D-D, as thedrug in the polymer is released, delivery zones 80 formed around contactpoints 82 do not significantly overlap. As a result, the tissue areaadjacent to delivery zones 80 receives a more uniform amount of drug.

Methods of Varying Drug Concentration

The drug concentration on the stent can be varied by using differentapproaches. For ease of discussion, the following describes how to varythe drug concentration along the length of the stent. However, one ofordinary skill in the art will understand that these same approaches canalso be used to vary the drug concentration along the circumference ofthe stent or along individual structural members such as the struts.

In one embodiment, struts 52 and connecting elements 54 can have depots56 for containing a drug. By varying the number of depots along thelength of stent 40, the drug concentration can be varied along thelength of stent 40. For instance, as shown in the enlarged windows ofFIG. 4, struts 52 and connecting elements 54 in third segment 46 cancontain the most number of depots 56, whereas struts 52 and connectingelements 54 located in first segment 42 contain the least.Alternatively, depots 56 of third segment 46 can be formed to containthe largest volume of the drug and depots 56 of first segment 42 can beformed to contain the smallest volume of drug. The volume of depot 56can be increased by increasing the depth and/or diameter of depot 56.

Depots 56 may have a depth of about one half of the thickness of struts52 or connecting elements 54 at the location of depots 56. For example,depots 56 can have a depth of about 60-80 microns. Depots can takevarious shapes, with representative shapes including a truncated coneshape or a dimple shape.

Depots can be formed using any suitable etching technique known to onehaving ordinary skill in the art such as chemical etching. Chemicaletching is a manufacturing technique whereby selected portions of ametal surface are blanked or dissolved away using a chemical etchant oran acid. The desired placement of depots 56 can be performed byphysically protecting portions of the stent material. Anotherrepresentative example of a method of forming depots 56 includes usinglasers, such as excimer lasers and Nd:YAG (neodymium yttrium aluminumgarnet) lasers.

In another embodiment, the drug concentration on the stents can bevaried by modifying the surface of the stents in order to increase thesurface area of the stents. In other words, the surface area of thestents can be roughened to provide an irregular surface area and whenthe polymeric drug coating is applied, the drug concentration variesalong the length of the stent because more coating can be applied to theportions of the stent which have a greater surface area than the otherportions of the stent. In one embodiment, the roughness factor (h_(r))gradually or incrementally changes along the entire length of stent 40.

For instance, for a length of strut 52 or connecting element 54, asurface area (γ) is provided which is given by the equation:γ=2πrlh_(r), where r is a radius (r) of strut 52 or connecting element54, l is a length (l) of the segment of strut 52 or connecting element54, and h_(r) is the roughness factor (h_(r)) (i.e., degree ofroughness) of the segment. If the surface is entirely smooth, theroughness factor (h_(r)) is 1.0. However, if the surface area isroughened, then the roughness factor (h_(r)) is greater than 1.0. Ifsurface area (γ) varies throughout a given length (l) then the drugconcentration will vary throughout that same length (l). Given theequation γ=2πrlh_(r), it can be seen that if the variable h_(r) of theequation fluctuates in value for the same given length (l), then so toowill the surface area (γ) of strut 52 or connecting element 54 withinthe given length (l). A change in the surface area along a given length(l) is given by the equation: γ′=2πrlΔh_(r). The drug concentrationdeliverable to biological vessel 12 is increased in correspondingportions of strut 52 or connecting element 54 where (h_(r)) is greaterthan 1.0.

Various methods can be used to increase the roughness factor (h_(r)).Representative examples include chemical, plasma, laser, mechanical orother methods of etching. For example, stent 40 can be dry etched bysand blasting or plasma etched with argon in order to increaseroughness. The roughness factor (h_(r)) on struts or connecting elementscan also be increased by a lithography technique. For example, acomposition including a polymer (e.g., ethylene vinyl alcohol copolymer)dissolved in a solvent can be applied to a stent. The solvent can thenbe essentially removed to form a polymeric coating. The stent can thenbe selectively treated with a solvent, such as dimethyl sulfoxide(DMSO), dimethyl formamide (DMF), or dimethyl acetamide (DMAC) to removeportions of the polymer coating.

In another embodiment, the drug concentration can be varied by providinga stent with variable structural dimensions so that the surface area ofthe struts and connecting elements is variable. For example, the radiusor thickness of struts 52 and connecting elements 54 can be varied alongthe length of stent 40 to provide a variable surface area. In oneembodiment, a surface area (γ) gradually or incrementally increasesalong the entire length of stent 40. The drug concentration, therefore,can gradually or incrementally increase along the entire length of stent40. Given the equation γ=2πrlh_(r), it can be seen that if the variabler of the equation fluctuates in value for the same given length (l),then so too will the surface area (γ) of strut 52 or connecting element54 within the given length (l). A change in the surface area along agiven length (l) is given by the equation: γ″=2πΔrlh_(r).

Stent 40 can be manufactured by using a laser to cut from, for example,a stainless steel tube. The laser cutting process can be run accordingto an automated process to form a particular stent configuration. Forexample, in order to increase radius (r) in particular struts 52 andconnecting elements 54, the automated process is programmed to cut withan increasing radius (r) along the length of stent 40 so that thesurface area (γ) ultimately changes gradually or incrementally from oneend of stent 40 to the other.

In another embodiment of the present invention, the drug concentrationon the stents can be varied by selective application of the polymericdrug coating composition. For example, stent 40 can be selectivelydipped in multiple repetitions so that the coating is less thick orabsent from particular segments of stent 40. By using a selectivedipping process, the thickness of the coating can gradually orincrementally increase from first end 48 to second end 50. Additionally,for example, a spray coater can be used to selectively apply thepolymeric drug coating to stent 40 so that the thickness of the coatingvaries along the length of the stent. Masks, for example, can be placedalong certain segments of the stent during a portion of the coatingprocess, thereby blocking the composition ejected from the spray coateralong these segments. By gradually moving the mask along the length ofthe stent during the spray application, the coating thickness can begradually increased from first end 48 to second end 50.

In another embodiment, the drug concentration on the stents can bevaried by changing the drug concentration in the composition during thecoating process. For example, during a spraying process, the amount of adrug can be gradually increased in the composition while the compositionis being sprayed onto the stent from one end of the stent to the other.

Methods of Varying the Release Rate

The release rate of the drug from the polymeric coating on the stent canbe varied by using different approaches. As with the previous section,for ease of discussion, the following describes how to vary the releaserate along the length of the stent. However, one of ordinary skill inthe art will understand that these same approaches can also be used tovary the release rate along the circumference of the stent or alongindividual structural members such as struts.

The release rate of the drug from the polymeric coating can be variedalong the length of the stent by varying the thickness of the coating.For example, if the thickness of the polymeric coating is gradually orincrementally decreased along the length of the stent while maintaininga constant drug concentration along the same length of stent, therelease rate of the drug will gradually or incrementally increase overthis length. For example, a stent coating could have a profile asdescribed in Table I.

TABLE I Coating Drug Thickness Concentration Drug Release Rate StentSegment (μm) (μg) (μg/hour) I 20 100 1 (distal segment) II 15 100 1.5(middle segment) III 10 100 2 (proximal segment)The drug release rate from the distal segment would be less than therelease rate from the middle and proximal segments because the drugwould have to diffuse through more polymer. The thickness of the coatingcan be varied while maintaining a constant drug concentration by varyingthe drug concentration during multiple spray applications in combinationwith a masking technique. For example, for the application of thecoating of Table I, the following application process could be applied:

TABLE II Drug Spray Coating Applied to Concentration in ApplicationSegment Masked Stent (μm) the Composition First II and III 20 n Second Iand III 15 1.5n Third I and II 10 2n

The release rate of the drug from the polymeric coating can also bevaried along the length of the stent by varying the thickness ofparticular regions of the coating. For example, the polymeric coatingcould have a reservoir region that contains the drug, and a diffusionbarrier layer that is substantially free from drug and reduces therelease rate of the drug from the coating. The release rate can bevaried along the length of the stent by varying the thickness of thebarrier layer along the length of the stent, for example, by maskingportions of the stent during spray application.

The release rate can also be varied by using different polymers thathave different drug permeabilities along the length of the stent. Forexample, if the reservoir layer is constructed of a polymer A (e.g.,ethylene vinyl alcohol copolymer) that produces a higher release ratethan a reservoir layer constructed of polymer B (with the samethickness) (e.g., polybutylmethacrylate), then the release rate can bevaried by using pure polymer A at particular segments of stent 40 andpure polymer B at other segments. The release rate can be varied alongthe length of stent 40 by mixing varying amounts of polymer A and Balong the length. One skilled in the art will understand that therelease rate will be determined in part by the diffusion rate of thedrug in the particular polymer or polymers used in the coating.

Embodiments of the Composition

The composition for the coating can include a solvent, a polymerdissolved in the solvent and a drug. The composition can be applied tothe surface of the stent by any conventional means, and a final heattreatment can be conducted to remove essentially all of the solvent fromthe composition to form the coating.

Representative examples of polymers that can be used to coat a stent inaccordance with the present invention include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOH or by the trade nameEVAL), poly(hydroxyvalerate); poly(L-lactic acid); polycaprolactone;poly(lactide-co-glycolide); poly(hydroxybutyrate);poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester;polyanhydride; poly(glycolic acid); poly(D,L-lactic acid); poly(glycolicacid-co-trimethylene carbonate); polyphosphoester; polyphosphoesterurethane; poly(amino acids); cyanoacrylates; poly(trimethylenecarbonate); poly(iminocarbonate); copoly(ether-esters) (e.g. PEO/PLA);polyalkylene oxalates; polyphosphazenes; biomolecules, such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid;polyurethanes; silicones; polyesters; polyolefins; polyisobutylene andethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinylhalide polymers and copolymers, such as polyvinyl chloride; polyvinylethers, such as polyvinyl methyl ether; polyvinylidene halides, such aspolyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile;polyvinyl ketones; polyvinyl aromatics, such as polystyrene; polyvinylesters, such as polyvinyl acetate; copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins; polyurethanes; polybutylmethacrylate; rayon; rayon-triacetate;cellulose acetate; cellulose butyrate; cellulose acetate butyrate;cellophane; cellulose nitrate; cellulose propionate; cellulose ethers;and carboxymethyl cellulose.

“Solvent” is defined as a liquid substance or composition that iscompatible with the polymer and is capable of dissolving the polymer atthe concentration desired in the composition. Representative examples ofsolvents include chloroform, acetone, water (buffered saline),dimethylsulfoxide (DMSO), propylene glycol methyl ether (PM,)iso-propylalcohol (IPA), n-propylalcohol, methanol, ethanol,tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide(DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane,nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate,isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol,2-butanone, cyclohexanone, dioxane, methylene chloride, carbontetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene,1,1,1-trichloroethane, formamide, hexafluoroisopropanol,1,1,1-trifluoroethanol, and hexamethyl phosphoramide and a combinationthereof.

The drug contained in the coating can be for inhibiting the activity ofvascular smooth muscle cells. More specifically, the drug can be aimedat inhibiting abnormal or inappropriate migration and/or proliferationof smooth muscle cells for the inhibition of restenosis. The drug canalso include any substance capable of exerting a therapeutic orprophylactic effect in the practice of the present invention. Forexample, the drug can be for enhancing wound healing in a vascular siteor improving the structural and elastic properties of the vascular site.Examples of drugs include antiproliferative substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; orCOSMEGEN available from Merck). Synonyms of actinomycin D includedactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁, andactinomycin C₁. The drug can also fall under the genus ofantineoplastic, antiinflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antiallergic andantioxidant substances. Examples of such antineoplastics and/orantimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis S. A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin®from Pharmacia & Upjohn, Peapack, N.J.), and mitomycin (e.g. Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.) Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.) Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, tacrolimus, dexamethasone, and rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUSavailable from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

The dosage or concentration of the drug required to produce a favorabletherapeutic effect should be less than the level at which the drugproduces toxic effects and greater than the level at whichnon-therapeutic results are obtained. The dosage or concentration of thedrug required to inhibit the desired cellular activity of the vascularregion can depend upon factors such as the particular circumstances ofthe patient; the nature of the trauma; the nature of the therapydesired; the time over which the ingredient administered resides at thevascular site; and if other drugs are employed, the nature and type ofthe substance or combination of substances. Therapeutic effectivedosages can be determined empirically, for example by infusing vesselsfrom suitable animal model systems and using immunohistochemical,fluorescent or electron microscopy methods to detect the agent and itseffects, or by conducting suitable in vitro studies. Standardpharmacological test procedures to determine dosages are understood byone of ordinary skill in the art.

Optional Coating Layers

An optional primer layer can be formed prior to the reservoir coating(i.e., the coating containing the drug) to increase the retention of thereservoir coating on the surface of the stent, particularly metallicsurfaces such as stainless steel. The primer layer can act as anintermediary adhesive tie layer between the surface of the device andthe reservoir coating, allowing for the quantity of the drug to beincreased in the reservoir coating. In addition, an optional diffusionbarrier can be formed over the reservoir coating to reduce the rate atwhich the drug is released from the coated stent.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of coating a stent, comprising: applying a compositionincluding a drug and a polymer to the stent to form a coating, whereinthe release rate of the drug from the coating gradually increases alonga length of the stent, the length extending axially from opposite endsof the stent.
 2. The method of claim 1, wherein the composition isapplied so that a thickness of the coating decreases along the length ofthe stent.
 3. The method of claim 2, wherein the thickness of thecoating is varied along the length of the stent by masking portions ofthe stent during the applying of the composition.
 4. The method of claim1, further comprising applying to the stent a barrier region over thecomposition, the barrier region is applied so that the thickness of thebarrier region decreases along the length of the stent.
 5. The method ofclaim 1, wherein the coating comprises different polymers havingdifferent drug permeabilities along the length of the stent.